The Effect of Ibuprofen Exposure and Patient Characteristics on the Closure of the Patent Ductus Arteriosus in Preterm Infants

Spontaneous closure of the ductus arteriosus depends on gestational age (GA) and might be delayed in preterm infants, resulting in patent ductus arteriosus (PDA). Ibuprofen can be administered to enhance closure, but the exposure‐response relationship between ibuprofen and the closure of PDA remains uncertain. We investigated the influence of patient characteristics and ibuprofen exposure on ductus closure. A cohort of preterm infants with PDA and treated with ibuprofen was analyzed. Ibuprofen exposure was based on a previously developed population pharmacokinetic study that was in part based on the same study population. Logistic regression analyses were performed with ductus closure (yes/no) as outcome, to analyze the contribution of ibuprofen exposure and patient characteristics. In our cohort of 263 preterm infants (median GA 26.1 (range: 23.7–30.0) weeks, birthweight 840 (365–1,470) g) receiving ibuprofen treatment consisting of 3 doses that was initiated at a median postnatal age (PNA(start)) of 5 (1–32) days, PDA was closed in 55 (21%) patients. Exposure to ibuprofen strongly decreased with PNA(start). Overall, the probability of ductus closure decreased with PNA(start) (odds ratio (OR): 0.7, 95% CI: 0.6–0.8) and Z‐score for birthweight (Z (Birthweight‐for‐GA); OR: 0.8, 95% CI: 0.6‐1.0), and increased with GA (OR: 1.5, 95% CI: 1.1–1.9). For patients with PNA(start) < 1 week, concentrations of ibuprofen, GA, and Z (Birthweight‐for‐GA) predicted probability of ductus closure. During a window of opportunity for ductus closure within the first days of life, probability of closure depends on GA, Z (Birthweight‐for‐GA), and ibuprofen exposure. Increased, yet unstudied dosages might increase the effectivity of ibuprofen beyond the first week of life.